Treatment Options
Benzodiazepine Receptor Agonists
Benzodiazepine receptor agonists can be considered as one of two types – those that have a benzodiazepine structure (see Figure 1), ‘benzodiazepines’, and those that do not have a benzodiazepine structure ‘z’-drugs.1
Benzodiazepines were the cornerstone of insomnia treatment prior to the 1990s. The top-selling benzodiazepines are:
- lormetazepam
- triazolam
- temazepam
- brotizolam
- nitrazepam
- flunitrazepam.
Others include flurazepam, quazepam, loprazolam, and estazolam. These drugs are still prescribed, but their use has declined following reported concerns over their association with abuse, dependence, cognitive and psychomotor impairment, and residual effects.2-4 This includes a marked reduction in popularity of diazepam (valium) one of the most well known members of the benzodiazepine group.
The ‘z’-drugs were first introduced in the 1990s, with the aim of providing the same efficacy as the benzodiazepines, but with an improved safety profile.2 Because of their specific mechanism of action (see below), the ‘z’-drugs have a more sleep-focused effect, and have, to a large extent, replaced benzodiazepines for the treatment of insomnia.2 Although the safety profile of ‘z’-drugs is more favourable compared with the benzodiazepines, the alleged lack of tolerance and potential for abuse has not been upheld in clinical practice. As such, warnings as to the potential for dependence, tolerance, abuse, and withdrawal effects have been included in the prescribing information for a selection of the ‘z’-drugs. The group of ‘z’-drugs comprises:
- zolpidem
- zaleplon
- zopiclone
- eszopiclone (the S-enantiomer of zopiclone), hence the ‘z’-drug label.
In both the benzodiazepine and ‘z’-drug groups, the individual drugs vary in their duration of action as reflected in the length of the half-life (see Table 1), such that those with a shorter half-life have a shorter duration of action and vice versa.
| Benzodiazepines | ‘z’-drugs | ||
|---|---|---|---|
| Generic name | Half-life (hr) | Generic name | Half-life (hr) |
| Lormetazepam | 10–12b | Zolpidem (Ambien PI, 2008) |
2.5 (2.9 in elderly) |
| Triazolam (Halcion PI, 2008) |
1.5–5.5 | Zolpidem ER (Ambien CR PI, 2008) |
2.8 (2.9 in elderly) |
| Temazepam (Restoril PI, 2008) |
8.8 | Zaleplon (Sonata PI, 2008) |
~1.0 |
| Brotizolam | 6–7b | Zopiclone | 5–6b |
| Nitrazepam | 15–38b | Eszopiclone (Lunesta PI, 2008) |
6.0 (9.0 in elderly) |
| Flunitrazepam (Dalmane PI, 2008) |
18–26b (36–200)a |
||
| Flurazepam | 47–100a | ||
| Quazepam (Doral PI, 2008) |
39–73a | ||
| Estazolam (ProSom PI, 2008) |
10–24 | ||
References:
1. National Institute of Health. NIH State of the Science Conference statement on manifestations and management of chronic insomnia in adults statement. J Clin Sleep Med 2005; 1 (4): 412–421.
2. Lieberman JA. Update on the safety considerations in the management ofinsomnia with hypnotics: incorporating modified- release formulations into primary care. Prim Care Companion J Clin Psychiatry 2007; 9 (1): 25
3. Kales A, Scharf MB, Kales JD, Soldatos CR. Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines. JAMA 1979; 241 (16): 1692–1695.
4. Tansella CZ, Tansella M, Lader M. A comparison of the clinical and psychological effects of diazepam and amylobarbitone in anxious patients. Br J Clin Pharmacol 1979; 7 (6): 605–611.